A major focus of cancer immunology is on the isolation of antibodies that react selectively with human tumor cells, since the antibodies could have important applications for targeting diagnostic and therapeutic agents to tumors and for identifying tumorigenic antigens. The established approach has been to generate large panels of monoclonal antibodies from mice immunized with human tumor cells, and to screen the antibodies for reactivity against the tumor. Despite the enormous effort expended on this approach, few antibodies that react preferentially with human tumors, and none that react specifically with one type of tumor, have been reported.
These results are disappointing but not necessarily conclusive, because the antibodies were generated in an xenogeneic system. Human antigens are generally recognized as foreign by the murine system, and since the tumor antigens are predominately nonspecific, the murine response to human tumors will be correspondingly nonspecific.
Another approach involves generating human monoclonal antibodies from cancer patients by cloning lymphocytes transformed with Epstein-Barr virus or fused with myeloma or B-lymphoblastoid cells. However, the number of clones that can be produced with these procedures is severely limited by technical obstacles, and the antibodies isolated from the clones have shown specificities similar to those obtained with murine monoclonal antibodies.
Further attempts to isolate more specific antibodies will require improved methods of generating and selecting antibodies against human tumors. Two recent developments may be useful in this regard. One involves immunizing cancer patients with autologous tumor cells which have been genetically modified to boost the immunogenicity of the cells (Dranoff, G. & Mulligan, R. C. (1995) Adv. Immunol. 58, 417-454). Although there is an extensive normal human repertoire of anti-self antibodies (Griffiths A. D., et al., (1993) EMBO J 12, 725-734), indicating that the human immune system can respond toself antigens, the humoral response of the immunized cancer patients might be directed preferentially against any non-self antigens expressed by the autologous or allogeneic tumor cells. Numerous such immunization trials are in progress with melanoma, renal and colon carcinoma, neuroblastoma and breast cancer patients, and others are planned.
The other new development is the introduction of methods for synthesizing virtually the entire repertoire of any person's antibody genes, and for expressing the encoded Fab or scFv antibody fragments on the surface of a fusion-phage vector (see, for example, Marks, J., et al., (1991) J. Mol. Biol. 222, 581-597). The resulting fusion-phage antibody library can be panned to select and clone rare antibodies on the basis of their binding specificities.